Mixtures or organic compounds for the treatment of airway diseases

ABSTRACT

A medicament comprising, separately or together, (A) a compound of formula (I) in free or pharmaceutically acceptable salt or solvate form and (B) a corticosteroid, for simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease, the molar ratio of (A) to (B) being from 100:1 to 1:300.

This invention relates to organic compounds and their use aspharmaceuticals, in particular for the treatment of inflammatory orobstructive airways diseases.

In one aspect, the present invention provides a medicament comprising,separately or together, (A) a compound of formula

in free or pharmaceutically acceptable salt or solvate form and (B) acorticosteroid, for simultaneous, sequential or separate administrationin the treatment of an inflammatory or obstructive airways disease.

In another aspect, the present invention provides a method of treatingan inflammatory or obstructive airways disease which comprisesadministering to a subject in need of such treatment effective amountsof (A) as hereinbefore defined and (B) as hereinbefore defined.

In a further aspect, the present invention provides a pharamceuticalcomposition comprising a mixture of effective amounts of (A) ashereinbefore defined and (B) as hereinbefore defined, optionallytogether with at least one pharmaceutically acceptable carrier.

The invention further provides the use of (A) as hereinbefore definedand/or (B) as hereinbefore defined in the preparation of a medicamentfor combination therapy by simultaneous, sequential or separateadministration of (A) and (B) in the treatment of an inflammatory orobstructive airways disease.

The compound of formula I may be prepared in free or salt or solvateform by reacting (R)-8-benzyloxy-5-oxranylcarbostyril with5,6-diethylindan-2-ylamine to give8-benzyloxy-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one,subjecting the latter to a deprotecting reaction to replace the benzylgroup by hydrogen, and recovering the resultant compound of formula I infree or salt or solvate form. The reactions may be carried out using theprocedures hereinafter described in the Examples or analogousprocedures. (R)-8-benzyloxy-5-oxiranylcarbostyril may be prepared asdescribed in WO95/25104. 5,6-Diethylindan-2-ylamine may be prepared byknown methods or analogues thereof, for example as described hereinafterin the Examples.

Pharmaceutically acceptable salts of the compound of formula I may beacid addition salts, including those of inorganic acids, for examplehydrohalic acids such as hydrofluoric acid, hydrochloric acid,hydrobromic acid or hydriodic acid, nitric acid, sulfuric acid,phosphoric acid; and organic acids such as formic acid, acetic acid,propionic acid, butyric acid, benzoic acid, o-hydroxybenzoic acid,p-hydroxybenzoic acid, p-chlorobenzoic acid, diphenylacetic acid,triphenylacetic acid, 1-hydroxynaphthalene-2-carboxylic acid,3-hydroxynaphthalene-2-carboxylic acid, aliphatic hydroxy acids such aslactic acid, citric acid, tartaric acid or malic acid, dicarboxylicacids such as fumaric acid, maleic acid or succinc acid, and sulfonicacids such as methanesulfonic acid or benzenesulfonic acid. These saltsmay be prepared from compounds of formula I by known salt-formingprocedures. Pharmaceutically acceptable solvates are generally hydrates.A particularly preferred form of the compound of Formula I is themaleate salt.

The corticosteroid (B) may be, for example, of formula

or a 1,2-dihydro derivative thereof, where

-   R¹ is C₁-C₄-alkyl optionally substituted by halogen (preferably    chlorine or fluorine), hydroxy, C₁-C₄-alkoxy, acyloxy or by    acylthio, ox R¹ is C₁-C₄-alkoxy or C₁-C₄-alkylthio optionally    substituted by halogen, or R¹ is 5-or 6-membered heterocyclylthio,-   either R² is acyloxy and R³ is hydrogen or C₁₋₄-alkyl, or R² and R³    together denote a group of formula    where R⁴ is C₁-C₄-alkyl or C₃₋₆-cycloalkyl and R⁵ is hydrogen or    C₁-C₄-alkyl, and X¹ and x² are each independently hydrogen, chlorine    or fluorine.

C₁-C₄-alkyl as used herein may be methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl or tert-butyl.

C₁-C₄-alkoxy as used herein may be methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

C₁-C₄-alkylthio as used herein may be inethylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio ortert-butylthio.

When R¹ is acyloxy-substituted C₁-C₄-alkyl, the acyloxy group may be,for example, C₁-C₂₀-alkylcarbonyloxy, e.g. acetyloxy, n-propionyloxy,isopropionyloxy or hexadecanoyloxy, or C₃-C₆-cycloalkylcarbonyloxy, e.g.cyclohexylcarbonyloxy. When R¹ is acylthio-substituted C₁-C₄-alkyl, theacylthio group may be, for example, C₁-C₄-alkylcarbonylthio, e.g.acetylthio or n-propionylthio. When R¹ is 5-or-6-memberedheterocyclylthio, the heterocyclyl group may be an O-heterocyclyl group,for example a furanonyl group.

When R² is acyloxy, it may be, for example, C₁-C₄-alkylcarbonyloxy, e.g.acetyloxy, n-propionyloxy, or n-butyroyloxy, C₃-C₆-cycloalkylcarbonyloxye.g. cyclopropylcarbonyloxy, or 5-or 6-membered heterocyclylcarbonyloxye.g. furoyloxy.

When R³ is C₁-C₄-alkyl it may be in the alpha or beta conformation, moreusually in the alpha conformation.

When R² and R³ together denote a group of formula III, R⁴ asC₃-C₆-cycloalkyl may be, for example, cyclohexyl.

Corticosteroids of formula I and their 1,2-dihydro derivatives includebeclamethasone dipropionate, budesonide, fluticasone propionate,mometasone furoate, ciclesonide, triamcinolone acetonide, flunisolide,rofleponide palmitate, butixocort propionate and icometasone enbutate.In particularly preferred emodiments of the invention, thecorticosteroid (B) is budesonide, fluticasone propionate or mometasonefuroate.

Administration of the medicament or pharmaceutical composition ashereinbefore described, i.e. with (A) and (B) in admixture or separate,is preferably by inhalation, i.e. (A) and (B) or the mixture thereof arein inhalable form. The inhalable form of the medicament i.e. of (A)and/or (B) may be, for example, an atomizable composition such as anaerosol comprising the active ingredient, i.e. (A) and (B) separately orin admixture, in solution or dispersion in a propellant, or anebulizable composition comprising a solution or dispersion of theactive ingredient in an aqueous, organic or aqueous/organic medium. Forexample, the inhalable form of the medicament may be an aerosolcomprising a mixture of (A) and (B) in solution or dispersion in apropellant, or a combination of an aerosol containing (A) in solution ordispersion in a propellant with an aerosol containing (B) in solution ordispersion in a propellant. In another example, the inhalable form is anebulizable composition comprising a dispersion of (A) and (B) in anaqueous, organic or aqueous/organic medium, or a combination of adispersion of (A) in such a medium with a dispersion of (B) in such amedium.

An aerosol composition suitable for use as the inhalable form of themedicament may comprise the active ingredient in solution or dispersionin a propellant, which may be chosen from any of the propellants knownin the art. Suitable such propellants include hydrocarbons such asn-propane, n-butane or isobutane or mixtures of two or more suchhydrocarbons, and halogen-substituted hydrocarbons, for example chlorineand/or fluorine-substituted methanes, ethanes, propanes, butanes,cyclopropanes or cyclobutanes, such as dichlorodifluoromethane (CFC 12),trichlorofluoromethane (CFC11), 1,2-dichloro-1,1,2,2-tetrafluoroethane(CFC114) or, particularly, 1,1,1,2-tetrafluoroethane (HPA134a) and1,1,1,2,3,3,3-heptafluoropropane (HFA227), or mixtures of two or moresuch halogen-substituted hydrocarbons. Where the active ingredient ispresent in suspension in the propellant, i.e. where it is present inparticulate form dispersed in the propellant, the aerosol compositionmay also contain a lubricant and a surfactant, which may be chosen fromthose lubricants and surfactants known in the art. Other suitableaerosol compositions include surfactant-free or substantiallysurfactant-free aerosol compositions. The aerosol composition maycontain up to about 5% by weight, for example 0.0001 to 5%, 0.001 to 5%,0.001 to 3%, 0.001 to 2%, 0.001 to 1%, 0.001 to 0.1%, or 0.001 to 0.01%by weight of the active ingredient, based on the weight of thepropellant. Where present, the lubricant and surfactant may be in anamount up to 5% and 0.5% respectively by weight of the aerosolcomposition. The aerosol composition may also contain a co-solvent suchas ethanol in an amount up to 30% by weight of the composition,particularly for administration from a pressurised metered doseinhalation device. The aerosol composition may further contain a bulkingagent, for example a sugar such as lactose, sucrose, dextrose, mannitolor sorbitol, in an amount, for example, of up to 20%, usually 0.001 to1%, by weight of the composition.

In another embodiment of the invention, the inhalable form is a drypowder, i.e. (A) and/or (B) are present in a dry powder comprisingfinely divided (A) and/or (B) optionally together with at least oneparticulate pharmaceutically acceptable carrier, which may be one ormore materials known as pharmaceutically acceptable carriers, preferablychosen from materials known as carriers in dry powder inhalationcompositions, for example saccharides, including monosaccharides,disaccharides, polysaccharides and sugar alcohols such as arabinose,glucose, fructose, ribose, mannose, sucrose, trehalose, lactose,maltose, starches, dextran, mannitol or sorbitol. An especiallypreferred carrier is lactose. The dry powder may be contained as unitdoses in capsules of, for example, gelatin or plastic, or in blisters(e.g. of aluminium or plastic), for use in a dry powder inhalationdevice, which may be a single dose or multiple dose device, preferablyin dosage units of (A) and/or (B) together with the carrier in amountsto bring the total weight of powder per capsule to from 5 mg to 50 mg.Alternatively, the dry powder may be contained in a reservoir in amulti-dose dry powder inhalation device adapted to deliver, for example,3-25 mg of dry powder per actuation.

In the finely divided particulate form of the medicament, and in theaerosol composition where the active ingredient is present inparticulate form, the active ingredient may have an average particlediameter of up to about 10 μm, for example 0.1 to 5 μm, preferably 1 to5 μm. The particulate carrier, where present, generally has a maximumparticle diameter up to 300 μm, preferably up to 212 μm, andconveniently has a mean particle diameter of 40 to 100 μm, e.g. 50 to 75μm. The particle size of the active ingredient, and that of aparticulate carrier where present in dry powder compositions, can bereduced to the desired level by conventional methods, for example bygrinding in an airjet mill, ball mill or vibrator mill, sieving,microprecipitation, spray-drying, lyophilisation or controlledcrystallisation from conventional solvents or from supercritical media.

The inhalable medicament may be administered using an inhalation devicesuitable for the inhalable form, such devices being well known in theart. Accordingly, the invention also provides a pharmaceutical productcomprising a medicament or pharmaceutical composition as hereinbeforedescribed in inhalable form as hereinbefore described in associationwith one or more inhalation devices. In a further aspect, the inventionprovides an inhalation device, or a pack of two or more inhalationdevices, containing a medicament or pharmaceutical composition ashereinbefore described in inhalable form as hereinbefore described.

Where the inhalable form of the active ingredient is an aerosolcomposition, the inhalation device may be an aerosol vial provided witha valve adapted to deliver a metered dose, such as 10 to 100 μl, e.g. 25to 50 μl, of the composition, i.e. a device known as a metered doseinhaler. Suitable such aerosol vials and procedures for containingwithin them aerosol compositions under pressure are well known to thoseskilled in the art of inhalation therapy. For example, an aerosolcomposition may be administered from a coated can, for example asdescribed in EP-A-0642992. Where the inhalable form of the activeingredient is a nebulizable aqueous, organic or aqueous/organicdispersion, the inhalation device may be a known nebulizer, for examplea conventional pneumatic nebulizer such as an airjet nebulizer, or anultrasonic nebulizer, which may contain, for example, from 1 to 50 ml,commonly 1 to 10 ml, of the dispersion; or a hand-held nebulizer,sometimes referred to as a soft mist or soft spray inhaler, for examplean electronically controlled device such as an AERx (Aradigm, US) orAerodose (Aerogen), or a mechanical device such as a RESPIMAT(Boehringer Ingelheim) nebulizer which allows much smaller nebulizedvolumes, e.g. 10 to 100 μl, than conventional nebulizers. Where theinhalable form of the active ingredient is the finely dividedparticulate form, the inhalation device may be, for example, a drypowder inhalation device adapted to deliver dry powder from a capsule orblister containing a dry powder comprising a dosage unit of (A) and/or(B) or a multidose dry powder inhalation (MDPI) device adapted todeliver, for example, 3-25 mg of dry powder comprising a dosage unit of(A) and/or (B) per actuation. Suitable such dry powder inhalationdevices are well known. For example, a suitable device for delivery ofdry powder inencapsulated form is that described in US3991761, while asuitable MDPI device is that described in WO97/20589.

The medicament of the invention is preferably a pharmaceuticalcomposition comprising a mixture of (A) as hereinbefore defined and (B)as hereinbefore defined, preferably together with at least onepharmaceutically acceptable carrier as hereinbefore described.

The molar ratio of the compound (A) to the steroid (B) may be, ingeneral, from 100:1 to 1:300, for example from 50:1 to 1:100 or from20:1 to 1:50, preferably from 10:1 to 1:20, more preferably from 5:1 to1:10, from 3:1 to 1:7 or from 2:1 to 1:2. The compound (A) and thesteroid (B) may be administered separately in the same ratio.

A suitable daily dose of the compound (A), particularly as the maleatesalt, for inhalation may be from 20 kg to 2000 μg, for example from 20to 1500 μg, from 20 to 1000 μg preferably from 50 to 800 μg, e.g. from100 to 600 μg or from 100 to 500 μg. A suitable daily dose of steriod(B) for inhalation may be from 20 μg to 5000 μg, for example from 20 to4000 μg, from 50 to 3000 μg, from 50 to 2000 μg, from 50 to 1000 μg,from 50 to 500 μg, from 50 to 400 μg, from 50 to 300 μg, from 50 to 200μg or from 50 to 100 μg. Where (B) is budesonide, a suitable daily dosemay be from 25 to 4800 μg, for example from 25 to 4000 μg, from 25 to3200 μg, from 25 to 2400 μg, from 25 to 1600 μg, from 50 to 4800 μg,from 50 to 4000 μg, from 50 to 3200 μg, from 50 to 2400 μg, from 50 to1600 μg, from 100 to 4000 μf from 100 to 3200 μg, from 100 to 2400 μg,from 100 to 1600 μg, from 100 to 800 μg, from 100 to 400 μf from 200 to4000 μg, from 200 to 1600 μg, from 200 to 800 μg or from 200 to 400 μg,100 to 1600 μg being preferred. Where (B) is mometasone furoate, asuitable daily dose may be from 50 μg to 2000 μg, for example from 100to 200 μg, from 100 to 1600 μg from 100 to 1000 μg or from 100 to 800μg, preferably from 200 to 500 μg, for instance from 200 to 400 μg.Where (B) is fluticasone propionate, a suitable daily dose may be forinhalation may be from 25 to 2000 μg, for example from 25 to 1500 μg,from 25 to 1000 μg, from 25 to 500 μg from 25 to 250 μg, from 50 to 1500μg, from 50 to 1000 μg, from 50 to 500 μg, from 50 to 250 μg, from 100to 1500 μg, from 100 to 1000 μg, from 100 to 500 μg, from 100 to 2500μg, from 200 to 1500 μg, from 200 to 1000 μg or from 200 to 500 μg, 100to 1000 μg being preferred.

A suitable unit dose of compound (A), particularly as the maleate salt,may be from 20 to 2000 μg, for example from 20 to 1500 μg, from 20 to1000 μg, preferably from 50 to 800 μg, from 50 to 600 μg or from 50 to500 μg. A suitable unit dose of budesonide may be from 25 to 2400 μg,for example from 50 to 2400 μg, from 50 to 2000 μg, from 50 to 1600 μg,from 50 to 800 μg, from 50 to 400 μg, from 50 to 200 μg, from 100 to1600 μg, from 100 to 800 μg, from 100 to 400 μg, from 100 to 200 μg,from 200 to 1600 μg, from 200 to 800 μg or from 200 to 400 μg, 100 to400 μg being preferred. A suitable unit dose of mometasone furoate forinhalation may be from 25 to 200 μg, for example from 50 μg to 1500 μg,from 50 to 1000 μg, from 50 to 800 μg, from 50 to 400 μg, from 50 to 200μg, from 50 to 100 μg, from 100 to 800 μg, from 100 to 400 μg or from100 to 200 μg 100 to 400 μg being preferred. A suitable unit dose offluticasone propionate for inhalation may be from 25 to 1000 μg, forexample from 25 to 500 μg, from 25 to 250 μg, from 25 to 200 μg, from 50to 100 μg, from 50 to 500 μg, from 50 to 250 μg, from 50 to 200 μg, from100 to 1000 μg, from 100 to 500 μg, from 100 to 250 μg, from 100 to 200μg, from 150 to 500 μg or from 150 to 250 μg, 100 to 500 μg beingpreferred. These unit doses may be administered once or twice daily inaccordance with the daily doses mentioned hereinbefore. The precise unitand daily dose used will of course depend on the condition to betreated, the patient and the efficiency of the inhalation device.

In one preferred embodiment of the invention, the medicament of theinvention is a pharmaceutical composition which is a dry powder in acapsule containing a unit dose of (A) and (B), for example forinhalation from a single capsule inhaler, the capsule suitablycontaining a unit dose of (A) e.g. as hereinbefore described, and a unitdose of (B), e.g. as hereinbefore described, together with apharmaceutically acceptable carrier as hereinbefore described in anamount to bring the total weight of dry powder per capsule to between 5mg and 50 mg, for example 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35mg, 40 mg, 45 mg or 50 mg.

In another preferred embodiment of the invention, the medicament of theinvention is a pharmaceutical composition which is a dry powder foradministration from a reservoir of a multi-dose dry powder inhaleradapted to deliver, for example, 3 mg to 25 mg of powder containing aunit dose of (A) and (B) per actuation, for example, where (A) is in theform of the maleate salt, a powder comprising, by weight, 20 to 2000parts, for example 60 to 1000 parts, 100 to 500 parts, or 100 to 300parts of (A); 25 to 800 parts, e.g. 25 to 500 parts, 50 to 400 parts, or100 to 400 parts of (B); and 2000 to 25000 parts, e.g. 4000 to 15000parts or 4000 to 10000 parts of a pharmaceutically acceptable carrier ashereinbefore described.

In a further preferred embodiment of the invention, the medicament ofthe invention is a pharmaceutical composition which is an aerosolcomprising (A) and (B), e.g. in a ratio as hereinbefore described, in apropellant as hereinbefore described, optionally together with asurfactant and/or a bulking agent and/or a co-solvent such as ethanol ashereinbefore described, for administration from a metered dose inhaleradapted to deliver an amount of aerosol containing a unit dose of (A)and a unit dose of (B), or a known fraction of a unit dose of (A) and aknown fraction of a unit dose of (B), per actuation. Thus if, forexample, the inhaler delivers half of the unit doses of (A) and (B) peractuation, the unit doses can be administered by two actuations of theinhaler.

In accordance with the above, the invention also provides apharmaceutical kit comprising (A) and (B) as hereinbefore defined inseparate unit dosage forms, said forms being suitable for administrationof (A) and (B) in effective amounts. Such a kit suitably furthercomprises one or more inhalation devices for administration of (A) and(B). For example, the kit may comprise one or more dry powder inhalationdevices adapted to deliver dry powder from a capsule, together withcapsules containing a dry powder comprising a dosage unit of (A) andcapsules containing a dry powder comprising a dosage unit of (B). Inanother example, the kit may comprise a multidose dry powder inhalationdevice containing in the reservoir thereof a dry powder comprising (A)and a multidose dry powder inhalaiton device containing in the reservoirthereof a dry powder comprising (B). In a further example, the kit maycomprise a metered dose inhaler containing an aerosol comprisingcomprising (A) in a propellant and a metered dose inhaler containing anaerosol comprising (B) in a propellant.

The medicaments of the invention are advantageous in the treatment ofinflammatory or obstructive airways disease, exhibiting highly effectivebronchodilatory and anti-inflammatory properties. For instance, it ispossible using the combination therapy of the invention to reduce thedosages of corticosteroid required for a given therapeutic effectcompared with those required using treatment with a corticosteroidalone, thereby minimising possibly undesirable side effects. Inparticular, these combinations, particularly where (A) and (B) are inthe same composition, facilitate achievement of a high anti-inflammatoryeffect, such that the amount of corticosteroid needed for a givenanti-inflammatory effect may be reduced when used in admixture with acompound of formula I; thereby reducing the risk of undesirable sideeffects from the repeated exposure to the steroid involved in thetreatment of inflammatory or obstructive airways diseases. Furthermore,using the combinations of the invention, particularly using compositionscontaining (A) and (B), medicaments which have a rapid onset of actionand a long duration of action may be prepared. Moreover, using suchcombination therapy, medicaments which result in a significantimprovement in lung function may be prepared. In another aspect, usingthe combination therapy of the invention, medicaments which provideeffective control of obstructive or inflammatory airways diseases, or areduction in exacerbations of such diseases, may be prepared. In afurther aspect, using compositions of the invention containing (A) and(B), medicaments which reduce or eliminate the need for treatment withshort-acting rescue medicaments such as salbutamol or terbutaline, maybe prepared; thus compositions of the invention containing (A) and (B)facilitate the treatment of an obstructive or inflammatory airwaysdisease with a single medicament.

Treatment of inflammatory or obstructive airways diseases in accordancewith thee invention may be symptomatic or prophylactic treatment.Inflammatory or obstructive airways diseases to which the presentinvention is applicable include asthma of whatever type or genesisincluding both intrinsic (non-allergic) asthma and extrinsic (allergic)asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma,exercise induced asthma, occupational asthma and asthma inducedfollowing bacterial infection. Treatment of asthma is also to beunderstood as embracing treatment of subjects, e.g. of less than 4 or 5years of age, exhibiting wheezing symptoms and diagnosed or diagnosableas “wheezy infants”, an established patient category of major medicalconcern and now often identified as incipient or early-phase asthmatics.(For convenience this particular asthmatic condition is referred to as“wheezy-infant syndrome”.)

Prophylactic efficacy in the treatment of asthma will be evidenced byreduced frequency or severity of symptomatic attack, e.g. of acuteasthmatic or bronchoconstrictor attack, improvement in lung function orimproved airways hyperreactivity. It may further be evidenced by reducedrequirement for other, symptomatic therapy, i.e. therapy for or intendedto restrict or abort symptomatic attack when it occurs, for exampleanti-inflammatory (e.g. corticosteroid) or bronchodilatory. Prophylacticbenefit in asthma may in particular be apparent in subjects prone to“morning dipping”. “Morning dipping” is a recognised asthmatic syndrome,common to a substantial percentage of asthmatics and characterised byasthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a timenormally substantially distant form any previously administeredsymptomatic asthma therapy.

Other inflammatory or obstructive airways diseases and conditions towhich the present invention is applicable include acute lung injury(AU), adult respiratory distress syndrome (ARDS), chronic obstructivepulmonary, airways or lung disease (COPD, COAD or COID), includingchronic bronchitis and emphysema, bronchiectasis and exacerbation ofairways hyperreactivity consequent to other drug therapy, in particularother inhaled drug therapy. Further inflammatory or obstructive airwaysdiseases to which the present invention is applicable includepneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tobacosis and byssinosis.

The invention is illustrated by the following Examples, in which partsare by weight unless stated otherwise. In the Examples, Compound A isthe compound of formula I in the form of the maleate salt, Bud denotesbudesonide, FP denotes fluticasone propionate, MF denotes mometasonefuroate and OA denotes oleic acid (surfactant).

PREPARATION EXAMPLES

Preparation 1-3-chloro-1-(3,4-diethylphenyl)-1-propanone

1,2-Diethylbenzene (10.9 g, 74.6 mmol) and propionyl chloride (9.7 g,74.6 mmol) are added dropwise to AlCl₃ (22.3 g, 167.8 mmol) innitromethane (75 mL) over 30 min. The reaction mixture is stirred atroom temperature for 2 hours, after which 70 g of ice and 14 mLconcentrated sulphuric acid are added. The aqueous phase is extractedwith ether, and the combined organic phases extracted with 2N HCl andsaturated aqueous NaCl. The organic phase is further treated withactivated charcoal, magnesium sulphate, and filtered, and the solventremoved in vacuo.

1H-NMR (CDCl₃) ppm: 7.8 (1H, s, Ar); 7.7 (11, d, Ar); 7.2 (1H, d, Ar);3.9 (2H t, CH₂); 3.4 (2H, t, CH₂); 2.8 (4H, q, CH₂CH₃); 1.2 (6H, m,CH₃).

Preparation 2-5,6-diethyl-indan-1-one

3-chloro-1-(3,4-diethylphenyl)-1-propanone (15.5 g) is dissolved in 66ml concentrated sulphuric acid and heated to 90° C. for 4 hours. Thereaction mixture is cooled, ice (70 g) is added, and the aqueoussolution extracted twice with toluene. The organic layer is washed withsodium bicarbonate, saturated aqueous NaCl, and treated with activatedcharcoal and magnesium suphate. After filtration, the solvent is removedin vacuo. The product is purified by flash column chromatography(silica, hexane/ethylacetate 10:1), and further crystallised in hexane.

1H-NMR (CDCl₃) ppm: 7.6 (1H, s, Ar); 7.3 (1H, d, Ar); 3.1 (2H, m, CH₂);2.7 (6K, m, CH₂+CH₂CH₃); 1.2 (6, m, CH₃).

Preparation 3-5,6-Diethyl-indan-1,2-dione 2-oxime

5,6-diethyl-indan-1-one (5 g, 26 mmol) in methanol (75 mL) is brought to40° C., n-butyl nitrite (3.0 g, 28.6 mmol) is added dropwise, followedby the addition of concentrated HCl (1.25 mL). After 1 hour, thereaction is brought to room temperature and the precipitated productfiltered off, washed with ice-cold methanol and dried.

1H-NMR (d6-DMSO) ppm: 12.6 (1H, s, OH); 7.4 (1H, s, Ar); 7.3 (1H, d,Ar); 3.6 (2H, s, CH₂); 2.6 (4H, m, CH₂CH₃); 1.1 (6H, m, CH₃).

Preparation 4-5,6-Diethyl-indan-2-ylamine hydrochloride

5,6-Diethyl-indan-1,2-dione 2-oxime (4.5 g) is added to a mixture ofacetic acid (150 mL), and concentrated sulphuric acid (4.5 mL). Pd/C 5%(1.5 g) is added, the reaction mixture degassed with nitrogen, andhydrogenated for 5 hours. The catalyst is then removed by filtration,the pH brought to pH 10 with 4M NaOH, and the solution extracted withchloroform. The organic phase is dried with magnesium sulphate, and thesolvent removed in vacuo. The residue is redisolved in a minimum amountof ether, and HCl saturated ether added. The white precipitate isfiltered and dried to yield the HCl salt of 5,6-diethyl-indan-2-ylamine.G

1H-NMR (d6-DMSO) ppm: 8.7 (3H, bd s, NH3); 7.3 (2H, s, Ar); 4.2 (1H, bds, CH); 3.5 (2H, dd, CH₂); 3.3 (2H, dd, CH₂); 2.8 (4H, q, CH₂CH); 1.4(6H, t, CH₃).

Preparation5—8-benzyloxy-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one

A solution of (R)-8-benzyloxy-5-oxiranylcarbostyril (5.00 g) and5,6-diethylindan-2-ylamine (3.87 g) in n-butanol is heated for 4 hoursat 110° C. After cooling to room temperature toluene (100 ml) is addedand the organic phase is washed with water (3×25 ml), loaded onto asilica gel chromatography column and eluted with toluene followed by amixture of toluene:ethanol:ethyl acetate:conc. ammonia (45:10:45:2) togive the title compound.

Preparation 6—Compound A:5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onemaleate

8-benzyloxy-5-[(R)2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one(360 mg) is dissolved in methanol (10 mL) and the compound isdeprotected by adding a catalytic amount of 10% palladium on charcoaland placing the solution under an atmosphere of hydrogen. The reactionis shown to be complete by TLC after 4 hours. The catalyst is filteredoff and the solvent is removed in vacuo. The product is taken up intoisopropanol and a solution of maleic acid in isopropanol added. Thetitle compound is obtained after recrystallisation from ethanol. TLC(silica, dichloromethane/methanol 10:1 R_(f)=0.05). ES+MS m/e 393 (MHz).

Examples 1-60

Gelatin capsules suitable for use in a capsule inhaler such as thatdescribed in U.S. Pat. No. 3,991,761 are prepared, each capsulecontaining a dry powder obtained by mixing Compound A and budesonidewhich have been ground to a mean particle diameter of 1 to 5 μm andlactose monohydrate having a particle diameter below 212 μm, the amountsbeing as shown in the table below: Compound A Budesonide Lactose Example(Parts) (Parts) (Parts) 1 20 100 19880 2 40 100 19860 3 80 100 19820 4100 100 19800 5 120 100 19780 6 140 100 19760 7 160 100 19740 8 180 10019720 9 200 100 19700 10 220 100 19680 11 240 100 19660 12 300 100 1960013 500 100 19400 14 1000 100 18900 15 2000 100 17900 16 20 100 24880 1740 100 24860 18 80 100 24820 19 100 100 24800 20 120 100 24780 21 140100 24760 22 160 100 24740 23 180 100 24720 24 200 100 24700 25 220 10024680 26 240 100 24660 27 300 100 24600 28 500 100 24400 29 1000 10023900 30 2000 100 22900 31 20 200 14780 32 40 200 14760 33 80 200 1472034 100 200 14700 35 120 200 14680 36 140 200 14660 37 160 200 14640 38180 200 14620 39 200 200 14600 40 220 200 14580 41 240 200 14560 42 300200 14500 43 500 200 14300 44 1000 200 13800 45 2000 200 12800 46 20 20024780 47 40 200 24760 48 80 200 24720 49 100 200 24700 50 120 200 2468051 140 200 24660 52 160 200 24640 53 180 200 24620 54 200 200 24600 55220 200 24580 56 240 200 24560 57 300 200 24500 58 500 200 24300 59 1000200 23800 60 2000 200 22800

Example 61-90

Examples 1-60 are repeated, but replacing the budesonide by mometasonefuroate, and using amounts as shown in the following table: Compound AMF Lactose Example (Parts) (Parts) (Parts) 61 20 100 24880 62 40 10024860 63 80 100 24820 64 100 100 24800 65 120 100 24780 66 140 100 2476067 160 100 24740 68 180 100 24720 69 200 100 24700 70 220 100 24680 71240 100 24660 72 300 100 24600 73 500 100 24400 74 1000 100 23900 752000 100 22900 76 20 200 14780 77 40 200 14760 78 80 200 14720 79 100200 14700 80 120 200 14680 81 140 200 14660 82 160 200 14640 83 180 20014620 84 200 200 14600 85 220 200 14580 86 240 200 14560 87 300 20014500 88 500 200 14300 89 1000 200 13800 90 2000 200 12800

Examples 91-135

A dry powder suitable for delivery from the reservoir of the multi-doseinhaler described in W097/20589 is prepared by mixing Compound A andfluticasone propionate which have been ground to a mean particlediameter of 1-5 μm and lactose monohydrate having a particle diameterbelow 212 μm, the amounts being as shown in the table below Compound AFP Lactose Example (Parts) (Parts) (Parts) 91 20 100 4880 92 40 100 486093 80 100 4820 94 100 100 4800 95 120 100 4780 96 140 100 4760 97 160100 4740 98 180 100 4720 99 200 100 4700 100 220 100 4680 101 240 1004660 102 300 100 4600 103 500 100 4400 104 1000 100 3900 105 2000 1002900 106 20 200 9780 107 40 200 9760 108 80 200 9720 109 100 200 9700110 120 200 9680 111 140 200 9660 112 160 200 9640 113 180 200 9620 114200 200 9600 115 220 200 9580 116 240 200 9560 117 300 200 9500 118 500200 9300 119 1000 200 8800 120 2000 200 7800 121 20 250 14730 122 40 25014710 123 80 250 14670 124 100 250 14650 125 120 250 14630 126 140 25014610 127 160 250 14590 128 180 250 14570 129 200 250 14550 130 220 25014530 131 240 250 14510 132 300 250 14450 133 500 250 14250 134 1000 25013750 135 2000 250 12750

Examples 136-163

Aerosol formulations are prepared by dispensing micronised activeingredients and, if required, lactose as bulking agent into a vial,sealing the vial with a metering valve, injecting the premixedethanol/propellant and optional surfactant into the vial through thevalve and subjecting the vial to ultrasonic energy to disperse the solidparticles. The components and amounts used are shown in the followingtables: Cpd. A HFA134a HFA227 OA Lactose Ex. (Parts) MF (Parts) (Parts)(Parts) Ethanol (Parts) (Parts) (Parts) 136 2 10 36500 60750 2500 — 70137 4 10 3410 6340 230 0.3 — 138 8 10 97000 — 2500 — 90 139 10 10 3050067000 2500 0.5 100 140 12 10 3150 6550 250 1 — 141 14 10 3700 6050 2500.8 — 142 16 10 3800 5900 230 0.4 — 143 18 10 4700 5050 250 1 — 144 2020 3600 6150 225 1 — 145 22 20 3500 6200 230 1 — 146 24 20 98000 — 25001 — 147 30 20 3900 5900 250 1 — 148 2 20 30000 67000 2250 0.2 90 149 1020 3500 6200 250 0.5 — 150 14 20 3200 6500 230 1 — 151 18 20 3100 6200225 0.8 — 152 20 20 3150 6100 225 1 — 153 24 20 30000 60000 2000 0.8 —Cpd. A HFA134a HFA227 OA Lactose Ex. (Parts) FP (Parts) (Parts) (Parts)Ethanol (Parts) (Parts) (Parts) 154 4 10 34000 63000 2250 0.3 50 155 810 92000 — 2500 0.5 70 156 12 10 3000 5500 200 — — 157 16 10 2500 5000200 0.3 — 158 20 10 2000 3000 150 0.2 — 159 30 10 2000 2000 150 0.2 —160 8 20 20000 25000 1500 0.2 — 161 12 20 2500 2500 200 0.2 — 162 20 202000 2000 150 0.2 — 163 30 20 20000 20000 1500 0.2 —

Examples 164-199

The procedure of Examples 91-135 is repeated, but replacing fluticasonepropionate by mometasone furoate, and using amounts as shown in thefollowing table. Compound A MF Lactose Example (Parts) (Parts) (Parts)164 100 100 4800 165 200 100 4700 166 300 100 4600 167 400 100 4500 168500 100 4400 169 600 100 4300 170 700 100 4200 171 800 100 4100 172 2000100 2900 173 100 200 4700 174 200 200 4600 175 300 200 4500 176 400 2004400 177 500 200 4300 178 600 200 4200 179 700 200 4100 180 800 200 4000181 1200 200 3600 182 100 400 4500 183 200 400 4400 184 300 400 4300 185400 400 4200 186 500 400 4100 187 600 400 4000 188 700 400 3900 189 800400 3800 190 100 100 9800 191 200 100 9700 192 300 100 9600 193 400 1009500 194 500 100 9400 195 100 200 9700 196 200 200 9600 197 300 200 9500198 400 200 9400 199 500 200 9300

Examples 200-236

The procedures of Examples 136-163 is repeated, but using the amountsshown in the following table, the ethanol being omitted in some of theExamples: Cpd. A HFA134a HFA227 OA Lactose Ex. (Parts) MF (Parts)(Parts) (Parts) Ethanol (Parts) (Parts) (Parts) 200 20 20 5000 — 200 0.5— 201 40 2 2500 2500 — — — 202 75 25 1500 3500 500 — 1 203 20 20 36006150 225 — 0.5 204 2 20 30000 67000 — — — 205 14 20 3200 6500 1500 — 4206 20 20 3150 6100 1500 4 — 207 10 20 4700 5050 500 — 0.2 208 60 2010000 10000 — — — 209 60 20 10000 10000 200 — — 210 60 20 10000 10000 —0.5 — 211 30 20 8000 12000 — 1 1 212 40 20 5000 15000 500 0.5 0.5 213 5020 9000 11000 400 0.8 0.2 214 20 20 4600 5000 400 0.4 0.2 215 30 1020000 25000 — — — 216 40 10 20000 30000 — — — 217 60 10 35000 65000 — —— Cpd. A FP HFA134a HFA227 Ethanol OA Lactose Ex. (Parts) (Parts)(Parts) (Parts) (Parts) (Parts) (Parts) 218 20 10 5000 5000 — — 1 219 1010 3650 6350 — — 1 220 30 10 3200 6800 100 0.5 0.5 221 30 20 7400 7600100 — — 222 40 20 8300 6700 200 0.5 — 223 60 20 3100 6900 300 1 — 224 1010 8000 12000 — — — 225 50 20 1600 3400 500 2 0.5 Cpd. A Bud HFA134aHFA227 Ethanol OA Lactose Ex. (Parts) (Parts) (Parts) (Parts) (Parts)(Parts) (Parts) 226 10 20 5500 4500 — — — 227 2 20 3500 6500 — — 1 228 120 2500 7500 — — 1 229 20 20 3800 6100 100 0.5 — 230 15 20 3300 6600 1000.5 0.5 231 30 20 3600 5900 500 4 — 232 40 20 4600 4900 500 3 — 233 3010 3100 6800 100 0.2 0.5 234 40 10 1400 3100 500 0.2 — 235 60 10 800012000 — — 1 236 80 10 30000 70000 — — —

Example 237-245

The procedure of Examples 136-163 is repeated, but using sorbitantrioleate (ST) as surfactant in place of oleic acid, the amounts of theingredients being as shown in the following table: Cpd. A HFA134a HFA227ST Lactose Ex. (Parts) MF (Parts) (Parts) (Parts) Ethanol (Parts)(Parts) (Parts) 237 60 40 10000 10000 300 4 — 238 60 20 8000 12000 200 8— 239 50 20 12000 8000 400 10 — 240 40 20 5000 5000 600 2.5 1 241 30 203500 6500 — 4 2 242 20 20 6000 4000 — 3 3 243 10 20 4500 5500 100 2 1244 20 10 4100 5900 50 1 2 245 15 5 1550 3450 200 0.5 1

1-20. (Cancelled).
 21. A medicament comprising, separately or together,(a) a compound

 in free or pharmaceutically acceptable salt or solvate form; and (b) acorticosteroid, for simultaneous, sequential or separate administrationin the treatment of an inflammatory or obstructive airways disease, themolar ratio of (a) to (b) being from 100:1 to 1:300.
 22. A medicamentaccording to claim 21, which is a pharmaceutical composition comprisinga mixture of effective amounts of (a) and (b) optionally together withat least one pharmaceutically acceptable carrier.
 23. A medicamentaccording to claim 21, in which (a) is a compound of formula (I) in theform of the maleate salt.
 24. A medicament according to claim 22, inwhich (a) is a compound of formula (I) in the form of the maleate salt.25. A medicament according to claim 21, in which the corticosteroid (b)is of formula (II)

or a 1,2-dihydro derivative thereof, where R¹ is C₁-C₄-alkyl optionallysubstituted by halogen, hydroxy, C₁-C₄-alkoxy, acyloxy or by acylthio,or R¹ is C₁-C₄-alkoxy or C₁-C₄-alkylthio optionally substituted byhalogen, or R¹ is 5- or 6-membered heterocyclylthio, either R² isacyloxy; and R³ is hydrogen or C₁-C₄-alkyl, or R² and R³ together denotea group of formula (III)

where R⁴ is C₁-C₄-alkyl or C₃-C₆-cycloalkyl; and R⁵ is hydrogen orC₁-C₄-alkyl; and X¹ and X² are each independently hydrogen, chlorine orfluorine.
 26. A medicament according to claim 22, in which thecorticosteroid (b) is of formula (II)

or a 1,2-dihydro derivative thereof, where R¹ is C₁-C₄-alkyl optionallysubstituted by halogen, hydroxy, C₁-C₄-alkoxy, acyloxy or by acylthio,or R¹ is C₁-C₄-alkoxy or C₁-C₄-alkylthio optionally substituted byhalogen, or R¹ is 5- or 6-membered heterocyclylthio, either R² isacyloxy; and R³ is hydrogen or C₁-C₄-alkyl, or R² and R³ together denotea group of formula (III)

 where R⁴ is C₁-C₄-alkyl or C₃-C₆-cycloalkyl; and R⁵ is hydrogen orC₁-C₄-alkyl; and X¹ and X² are each independently hydrogen, chlorine orfluorine.
 27. A medicament according to claim 21, in which thecorticosteroid (b) is beclamethasone dipropionate, budesonide,fluticasone propionate, mometasone furoate, ciclesonide, triamcinoloneacetonide, flunisolide, rofleponide palmitate, butixocort propionate oricometasone enbutate.
 28. A medicament according to claim 22, in whichthe corticosteroid (b) is beclamethasone dipropionate, budesonide,fluticasone propionate, mometasone furoate, ciclesonide, triamcinoloneacetonide, flunisolide, rofleponide palmitate, butixocort propionate oricometasone enbutate.
 29. A medicament according to claim 21, which isin inhalable form and is: (i) an aerosol comprising a mixture of (a) and(b) in solution or dispersion in a propellant; (ii) a combination of anaerosol containing (a) in solution or dispersion in a propellant with anaerosol containing (b) in solution or dispersion in a propellant; (iii)a nebulizable composition comprising a dispersion of (a) and (b) in anaqueous, organic or aqueous/organic medium; or (iv) a combination of adispersion of (a) in an aqueous, organic or aqueous/organic medium witha dispersion of (b) in an aqueous, organic or aqueous/organic medium.30. A medicament according to claim 21, in which (a) or (b), or (a) and(b), are present in inhalable form as a dry powder comprisingrespectively finely divided (a) or (b), or finely divided (a) and (b),optionally together with at least one particulate pharmaceuticallyacceptable carrier.
 31. A medicament according to claim 29, in which (a)or (b), or (a) and (b), has an average particle diameter up to 10 μm.32. A medicament according to claim 30, in which (a) or (b), or (a) and(b), has an average particle diameter up to 10 μm.
 33. A medicamentaccording to claim 21, in which the molar ratio of (a) to (b) is from5:1 to 1:10.
 34. A medicament according to claim 22, in which the molarratio of (a) to (b) is from 5:1 to 1:10.
 35. A medicament according toclaim 22, which is a dry powder in a capsule, the capsule containing aunit dose of (a), a unit dose of (b) and a pharmaceutically acceptablecarrier in an amount to bring the total weight of dry powder per capsuleto between 5 mg and 50 mg.
 36. A medicament according to claim 22, whichis a dry powder comprising, by weight, from 20 to 2000 parts of (a) inthe form of the maleate salt, from 25 to 800 parts of (b) and 2000 to25000 parts of a pharmaceutically acceptable carrier.
 37. A medicamentaccording to claim 22, which is an aerosol comprising (a) and (b), themolar ratio of (a) to (b) being from 5:1 to 1:10, in a propellant,optionally together with one or more components selected from asurfactant, a bulking agent and a co-solvent, suitable foradministration from a metered dose inhaler adapted to deliver an amountof aerosol containing a unit dose of (a) and a unit dose of (b), or aknown fraction of a unit dose of (a) and a known fraction of a unit doseof (b), per actuation.
 38. A method of treating an inflammatory orobstructive airways disease which comprises administering to a subjectin need of such treatment effective amounts of (a) and (b) as defined inclaim
 21. 39. A method of treating an inflammatory or obstructiveairways disease which comprises administering to a subject in need ofsuch treatment an effective amount of a medicament according to claim22.
 40. A pharmaceutical kit comprising (a) as defined in claim 21 and(b) as defined in claim 1 in separate unit dosage forms, said formsbeing suitable for administration of (a) and (b) in effective amounts,together with one or more inhalation devices for administration of (a)and (b).